5-Thia-omega-(substituted phenyl)-prostaglandin e alcohols, process for preparing the alcohols and pharmaceutical preparations containing the same as the active ingredient

ABSTRACT

A 5-thia-ω-substituted phenyl-prostaglandin E alcohol of the formula (I)  
                 
 
     (wherein, all the symbols are the same meanings as defined in the specification), a process for producing it and a pharmaceutical composition comprising it as an active ingredient.  
     The compounds of the formula (I) may be converted into carboxylic acids in the living body which can bind on PGE 2  receptors (especially, subtype EP 4 ) strongly, so the compounds of the formula (I) are expected to be useful for prevention and/or treatment of immunological diseases, asthma, abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still&#39;s disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn&#39;s disease, hypercytokinemia at dialysis, multiple organ failure, shock, sleeping disorder and blood platelet aggregation.

FIELD OF THE INVENTION

[0001] The present invention relates to a 5-thia-ω-substitutedphenyl-prostaglandin E alcohol.

[0002] More detail, it relates to a 5-thia-ω-substitutedphenyl-prostaglandin E alcohol of the formula (I)

[0003] (wherein, all the symbols are the same meaning as definedhereinafter), a process for producing it and a pharmaceuticalcomposition it as an active ingredient.

BACKGROUND

[0004] Prostaglandin E₂ (abbreviated as PGE₂) has been known as ametabolite in the arachidonate cascade. It has been known that PGE₂possesses cyto-protective activity, uterine contractile activity, apain-inducing effect, a promoting effect on digestive peristalsis, anawakening effect, a suppressive effect on gastric acid secretion,hypotensive activity and diuretic activity etc.

[0005] A recent study has proved existence of various PGE₂ subtypereceptors possessing a different physical role from each other. Atpresent, four receptor subtypes are known and they are called EP₁, EP₂,EP₃, EP₄ (Negishi M. et al, J. Lipid Mediators Cell Signaling, 12,379-391 (1995)).

[0006] It is thought that EP₄ subtype receptor relates to inhibition ofproducing TNF-α and acceleration of producing IL-10. Therefore, thecompounds which can bind on EP₄ subtype receptor strongly are expectedto be useful for the prevention and/or treatment of immunologicaldiseases (autoimmune diseases such as amyotrophic lateral sclerosis(ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosisand systemic lupus erythematosus etc., and rejection after organtransplantation etc.), asthma, abnormal bone formation, neuronal celldeath, lung failure, liver damage, acute hepatitis, nephritis, renalinsufficiency, hypertension, myocardiac ischemia, systemic inflammatoryresponse syndrome, sepsis, hemophagous syndrome, macrophage activationsyndrome, Still's disease, Kawasaki disease, burn, systemicgranulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia atdialysis, multiple organ failure, and shock etc. Further, it is thoughtthat EP₄ subtype receptor relates to sleeping disorder and bloodplatelet aggregation, so such compounds are expected to be useful forthe prevention and/or treatment of these diseases.

[0007] The present inventors et al. have found out that5-thia-prostaglandin derivatives of the following formula (A) are usefulas a compound which satisfies these purposes and have filed a patentapplication relates to such compounds (WO00/03980). These compounds canbind on EP₄ subtype receptor selectively and binds on the other subtypereceptors weakly, so they show no any other activities. Therefore theyare expected to be drugs possessing less side effects.5-Thia-ω-substituted phenyl-prostaglandin E derivatives of the followingformula (A):

[0008] (wherein, R^(1A) is hydroxy, C1-6 alkyloxy, or the formula:NR^(6A)R^(7A) (in which, R^(6A) and R^(7A) are, independently, hydrogenor C1-4 alkyl),

[0009] R² is oxo, halogen or the formula: O—COR^(8A) (in which, R^(8A)is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl)),

[0010] R^(3A) is hydrogen or hydroxy,

[0011] R^(4Aa) and R^(4Ab) are, independently, hydrogen or C1-4 alkyl,

[0012] R^(5A) is phenyl substituted with the following group:

[0013] i) 1-3 of substituent(s) selected from the group consisting of

[0014] C1-4 alkyloxy-C1-4 alkyl,

[0015] C2-4 alkenyloxy-C1-4 alkyl,

[0016] C2-4 alkynyloxy-C1-4 alkyl,

[0017] C3-7 cycloalkyloxy-C1-4 alkyl,

[0018] C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,

[0019] phenyloxy-C1-4 alkyl,

[0020] phenyl-C1-4 alkyloxy-C1-4 alkyl,

[0021] C1-4 alkylthio-C1-4 alkyl,

[0022] C2-4 alkenylthio-C1-4 alkyl,

[0023] C2-4 alkynylthio-C1-4 alkyl,

[0024] C3-7 cycloalkylthio-C1-4 alkyl,

[0025] C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl,

[0026] phenylthio-C1-4 alkyl, or

[0027] phenyl-C1-4 alkylthio-C1-4 alkyl,

[0028] ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,

[0029] C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,

[0030] C1-4 alkyloxy-C1-4 alkyl and hydroxy,

[0031] C1-4 alkyloxy-C1-4 alkyl and halogen,

[0032] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,

[0033] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,

[0034] C1-4 alkylthio-C1-4 alkyl and hydroxy, or

[0035] C1-4 alkylthio-C1-4 alkyl and halogen,

[0036] iii) haloalkyl or hydroxy-C1-4 alkyl, or

[0037] iv) C1-4 alkyl and hydroxy;

[0038]

is a single bond or a double bond, with the proviso that when R^(2A) isthe formula: O—COR^(8A), bond of C8-C9 is a double bond) andcyclodextrin clathrate thereof are described in the specification ofWO00/03980.

DISCLOSURE OF THE INVENTION

[0039] The present inventors et al. have studied to find out the stablecompounds which can bind on EP₄ subtype receptor specifically, and donot bind on any other EP subtype receptors nor any other prostanoidreceptors. The present inventors have found out 5-thiaprostaglandinwherein a substituted phenyl is introduced into ω-chain have achievedthis object, and then filed the said patent application (WO00/03980).

[0040] The present inventors et al. have confirmed that convertingcarboxy group of the compounds described in the said patent applicationinto hydroxy group (alcohol) improved an absorption of the compoundsinto the living body and then, have completed the present invention. Thecompounds of the formula (I) of the present invention may be convertedinto carboxylic acid which is an active compound by oxidation in theliving body. The said active carboxylic acid possesses an activity tobind on EP₄ subtype receptor strongly and bind on the other prostanoidreceptors including the other subtype receptors weakly, and a sufficientstability as a drug.

[0041] That is to say, the present invention relates to

[0042] (1) a 5-thia-ω-substituted phenyl-prostaglandin E alcohol of theformula (I)

[0043]  (wherein, --A-- is absent or --A-- is methylene or ethylene,

[0044] R¹ is hydrogen, C1-6 alkyl, phyenyl-C1-6 alkyl, C2-6 alkanoyl, orphyenyl-C2-6 alkanoyl,

[0045] R² is oxo or halogen,

[0046] R³ is hydrogen or hydroxy,

[0047] R^(4a) and R^(4b) are, independently, hydrogen or C1-4 alkyl,

[0048] R⁵ is phenyl substituted with the following group:

[0049] i) 1-3 of group selected from the group consisting of

[0050] C1-4 alkyloxy-C1-4 alkyl,

[0051] C2-4 alkenyloxy-C1-4 alkyl,

[0052] C2-4 alkynyloxy-C1-4 alkyl,

[0053] C3-7 cycloalkyloxy-C1-4 alkyl,

[0054] C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,

[0055] phenyloxy-C1-4 alkyl,

[0056] phyenyl-C1-4 alkyloxy-C1-4 alkyl,

[0057] C1-4 alkylthio-C1-4 alkyl,

[0058] C2-4 alkenylthio-C1-4 alkyl,

[0059] C2-4 alkynylthio-C1-4 alkyl,

[0060] C3-7 cycloalkylthio-C1-4 alkyl,

[0061] C3-7 cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl,

[0062] phenylthio-C1-4 alkyl, and

[0063] phyenyl-C1-4 alkylthio-C1-4 alkyl,

[0064] ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,

[0065] C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,

[0066] C1-4 alkyloxy-C1-4 alkyl and hydroxy,

[0067] C1-4 alkyloxy-C1-4 alkyl and halogen,

[0068] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,

[0069] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,

[0070] C1-4 alkylthio-C1-4 alkyl and hydroxy, or

[0071] C1-4 alkylthio-C1-4 alkyl and halogen,

[0072] iii) haloalkyl or hydroxy-C1-4 alkyl, or

[0073] iv) C1-4 alkyl and hydroxy;

[0074]

is a single bond or a double bond) or cyclodextrin clathrate thereof,

[0075] (2) a process for producing it and

[0076] (3) a pharmaceutical composition comprising it as an activeingredient.

[0077] In the formula (I), C1-4 alkyl in R^(4a), R^(4b)and R⁵ meansmethyl, ethyl, propyl, butyl and isomers thereof.

[0078] In the formula (I), C1-6 alkyl in R¹ means methyl, ethyl, propyl,butyl, pentyl, hexyl and isomers thereof.

[0079] In the formula (I), C2-6 alkyl in R¹ means ethyl, propyl, butyl,pentyl, hexyl and isomers thereof.

[0080] In the formula (I), C2-6 alkanoyl in R¹ means acetyl, propanoyl,butanoyl, pentanoyl, hexanoyl and isomers thereof.

[0081] In the formula (I), C2-4 alkenyl in R⁵ means vinyl, propenyl,butenyl and isomers thereof.

[0082] In the formula (I), C2-4 alkynyl in R⁵ means ethynyl, propynyl,butynyl and isomers thereof.

[0083] In the formula (I), C3-7 cycloalkyl in R⁵ means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0084] In the formula (I), halogen in R² and R⁵ means fluorine,chlorine, bromine and iodine.

[0085] In the present invention, the symbol

means single bond or double bond. Further, unless otherwise specified,in the present invention, the symbol

means that the substituent attached thereto is in front of the sheet,the symbol

means that the substituent attached thereto is behind the sheet and thesymbol

means that there is a mixture of substituents in front of and behind thesheet or that the substituent attached thereto may be in front of orbehind the sheet as would be clear to the person skilled in the art.

[0086] Unless otherwise specified, all isomers are included in thepresent invention. For example, alkyl, alkenyl, alkynyl, alkylene groupmeans straight-chain or branched-chain ones. In addition, isomers ondouble bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomersgenerated from asymmetric carbon atom(s) (R-, S-, α-, β-isomer,enantiomer, diastereomer), optically active isomers (D-, L-, d-,I-isomer), polar compounds generated by chromatographic separation (morepolar compound, less polar compound), equilibrium compounds, mixturesthereof at voluntary ratios and racemic mixtures are also included inthe present invention.

[0087] In the formula (I), the substituent(s) of phenyl in R⁵ ispreferably substituted at 3-position, 3-position and 4-position, and3-position and 5-position.

[0088] In the formula (I), each group (i) to (iv) as the substituent(s)of phenyl in R⁵ means as follows:

[0089] group i) means 1, 2 or 3 of alkyloxyalkyl etc.,

[0090] group ii) means at least one alkyloxyalkyl etc. and at least onealkyl, alkyloxy, hydroxy or halogen,

[0091] group iii) means alkyl substituted with 1 or 2 of halogen orhydroxy and

[0092] group iv) means at least one alkyl and at least one hydroxy.

[0093] Among the compounds of the present invention of the formula (I),the compounds described in the Examples, the compounds shown in thefollowing Tables are preferable. TABLE 1 (1)

R⁵

[0094] TABLE 2 (2)

R⁵

[0095] TABLE 3 (3)

R⁵

[0096] TABLE 4 (4)

R⁵

[0097] TABLE 5 (5)

R⁵

[0098] TABLE 6 (6)

R⁵

[0099] [Cyclodextrin Clathrate]

[0100] The compounds of the present invention of the formula (I) may beconverted into the corresponding cyclodextrin clathrates by the methoddescribed in the specification of Japanese Patent Application Kokoku Sho50-3362, 52-31404 or 61-52146 using α-, β- or γ-cyclodextrin or amixture thereof. Converting into the corresponding cyclodextrinclathrates serves to increase the stability and solubility in water ofthe compounds, and therefore it is useful in the use forpharmaceuticals.

[0101] [Process for Producing the Compounds of the Present Invention]

[0102] The compounds of the formula (I)

[0103] (wherein, all the symbols are the same meaning as definedhereinbefore) may be prepared from the compounds of the formula (II)

[0104] (wherein, R¹⁻¹ is C1-6 alkyl, phenyl-C1-6 alkyl, C2-6 alkanoyl,phenyl-C2-6 alkanoyl, or a protecting group of hydroxy which is removedunder an acidic condition,

[0105] R³⁻¹ is hydrogen or hydroxy group protected by a protecting groupof hydroxy which is removed under an acidic condition,

[0106] R¹⁰ is a protecting group of hydroxy which is removed under anacidic condition,

[0107] R⁵⁻¹ is the same meaning of R⁵ provided that hydroxy group in thegroup represented by R⁵⁻¹ is protected by a protecting group which isremoved under an acidic condition, and the other symbols are the samemeaning as defined hereinbefore)

[0108] by reaction for removal of a protecting group under an acidiccondition.

[0109] A protecting group of hydroxy which is removed under an acidiccondition includes, for example, t-butyldimethylsilyl, triphenylmethyl,and tetrahydropyran-2-yl (THP) etc.

[0110] Hydrolysis under an acidic condition has been known. Thisreaction may be carried out, for example, in an organic solvent which isadmissible with water (e.g., tetrahydrofran, methanol, ethanol,dimethoxyethane, acetonitrile or mixture thereof etc.), using aninorganic acid (e.g., hydrochloric acid, phosphoric acid, hydrofluoricacid, hydrogen fluoride-pyridine etc.) or an organic acid (e.g., aceticacid, tosylic acid, trichloroacetic acid etc.) at temperature of 0-50°C.

[0111] The compounds of the formula (II) may be prepared by thefollowing Reaction Schemes 1-3.

[0112] Each symbol in Reaction Schemes means as follows or same meaningdefined hereinbefore:

[0113] Ms: methanesulfony,

[0114] Ts: p-toluenesulfonyl,

[0115] R²⁻¹: halogen,

[0116] Ac: acetyl,

[0117] TMS: trimethylsilyl.

[0118] [Starting Materials and Reagents]

[0119] Each Reaction in the said Reaction Schemes may be carried out byknown methods. In the said Reaction Schemes, the compounds of theformulae (III), (V) and (XII) as starting materials have been known ormay be prepared easily by known methods.

[0120] For example, the compounds of the formula (III) wherein R³⁻¹ isTHP have been described in J. Am. Chem. Soc., 98, 1490 (1971).

[0121] The other starting materials and reagents in the presentinvention are known per se or may be prepared by known methods.

[0122] In each reaction in the present specification, reaction productsmay be purified by conventional techniques. For example, purificationmay be carried out by distillation at atmospheric or reduced pressure,by high performance liquid chromatography, by thin layer chromatographyor by column chromatography using silica gel or magnesium silicate, bywashing or by recrystallization. Purification may be carried out aftereach reaction, or after a series of reactions.

[0123] [Pharmacological Activities]

[0124] The compounds of the present invention of the formula (I) may beconverted into carboxylic acids by oxidation in the living body. Asdescribed in the specification of WO00/03980, the correspondingcarboxylic acids can bind strongly on EP₄ subtype receptor which is oneof PGE₂ receptors and show an activity on it.

[0125] For example, in the laboratory experiments, the inhibitory actionon producing TNF-α induced by lipopolysaccharide (LPS) or the conversionof the compounds of the present invention into carboxylic acids in theliving body has been confirmed by assaying the concentration in theblood plasma of rat.

[0126] [Inhibitory Action on Producing TNF-α]

[0127] LPS (10 μg/2 ml/kg) was administered into a tail vein ofSD-strain male rat. Blood was collected from an abdominal large veinwith heparin after 90 minutes from administration to prepare bloodplasma. The amount of TNF-α in the blood plasma was determined by usingELISA Kit (Rat TNF-α Immunoassay kit, Biosource Co.). Each compound ofthe present invention was administered orally before 30 minutes fromadministration of LPS. The effective dose (IC50) was defined as the doseat which the test compound showed 50% inhibition on producing TNF-α inblood plasma, when the amount of producing TNF-α in the control group(administration of LPS, non-administration of test compound) was as100%. The results are shown in Table 4. TABLE 4 Effective dose IC50Example No (μg/kg) p.o. 1 117 1(1) 57.4

[0128] [Converting into Carboxylic Acid in the Living Body]

[0129] The compound of Example 1(1) (1 mg/kg; alcohol compound) wasadministered into SD-strain male rat by intravenous route to determineeach concentration of the said compound and corresponding carboxylicacid, i.e., (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid (corresponding carboxylic acid) in blood plasma. The test solutionmay be prepared from a physiological saline solution containing 0.3%ethanol and 0.1% POLYSORBATE 80. The concentration was determined byusing liquid chromatograph mass spectrometer (LC/MS/MS). The results areshown in Table 5. TABLE 5 Concentration in blood plasma AUC_(0-∞)Compounds (ng · hr/ml) Example 1(1) 462 ± 78  corresponding 99 ± 26carboxylic acid

[0130] [Discussion]

[0131] It has been confirmed that the alcohol compounds which wereadministered into living body were converted into carboxylic acids in itby oxidation.

[0132] [Toxicity]

[0133] The toxicity of the compounds of the formula (I) of the presentinvention is very low and therefore, it is confirmed that thesecompounds are safe for use as medicine.

[0134] Industrial Application

[0135] [Application for Pharmaceuticals]

[0136] The compounds of the present invention of the formula (I) may beconverted into carboxylic acids by oxidation in the living body. Suchcarboxylic acids can bind on PGE₂ receptor and show the activity on it.Particularly, they bind on EP₄ subtype receptor strongly, so thecompounds of the formula (I) are expected to be useful for theprevention and/or treatment of immunological diseases (autoimmunediseases such as amyotrophic lateral sclerosis (ALS), multiplesclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemiclupus erythematosus etc., and rejection after organ transplantationetc.), asthma, abnormal bone formation, neuronal cell death, lungfailure, liver damage, acute hepatitis, nephritis, renal insufficiency,hypertension, myocardiac ischemia, systemic inflammatory responsesyndrome, sepsis, hemophagous syndrome, macrophage activation syndrome,Still's disease, Kawasaki disease, burn, systemic granulomatosis,ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis,multiple organ failure, and shock etc. Further, it is thought that EP⁴subtype receptor relates to sleeping disorder and blood plateletaggregation, so the compounds of the present invention are also expectedto be useful for the prevention and/or treatment of such diseases.

[0137] The carboxylic acids converted from the compounds of the presentinvention of the formula (I) by oxidation might bind weakly on thesubtypes receptors other than EP₄ subtype receptor do not express othereffects, therefore such compounds are expected to be an agent havingless side effect.

[0138] For the purpose above described, the compounds of the formula (I)of the present invention or cyclodextrin clathrate thereof may benormally administered systematically or locally, usually by oral orparenteral administration.

[0139] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 μg and 100mg, by oral administration, up to several times per day, and between 0.1μg and 10 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1 and 24hrs. per day into vein.

[0140] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases in which doses lower than orgreater than the ranges specified above may be used.

[0141] The compounds of the present invention may be administered assolid compositions, liquid compositions or other compositions for oraladministration, or as injections, liniments or suppositories etc. forparenteral administration.

[0142] Solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders, and granules etc.

[0143] Capsules contain hard capsules and soft capsules.

[0144] In such compositions, one or more of the active compound(s) is orare, admixed with at least one inert diluent such as lactose, mannitol,mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose,starch, polyvinylpyrrolidone, magnesium metasilicate aluminate.

[0145] The compositions may also comprise, as is normal practice,additional substances other than inert diluents: e.g. lubricating agentssuch as magnesium stearate, disintegrating agents such as cellulosecalcium glycolate, and assisting agents for dissolving such as glutamicacid, asparaginic acid. The tablets or pills may, if desired, be coatedwith film of gastric or enteric material such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or becoated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

[0146] Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, syrups and elixirsetc. In such liquid compositions, one or more of the active compound(s)is or are comprised in inert diluent(s) commonly used in the art (forexample, purified water, ethanol etc.). Besides inert diluents, suchcompositions may also comprise adjuvants such as wetting agents,suspending agents, sweetening agents, flavouring agents, perfumingagents and preserving agents.

[0147] Other compositions for oral administration include spraycompositions which may be prepared by known methods and which compriseone or more of the active compound(s). Spray compositions may compriseadditional substances other than inert diluents: e.g. stabilizing agentssuch as sodium hydrogen sulfate, stabilizing agents to give isotonicity,isotonic buffer such as sodium chloride, sodium citrate, citric acid.For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.

[0148] Injections for parenteral administration include sterile aqueousor non-aqueous solutions, suspensions and emulsions. Aqueous solutionsor suspensions include distilled water for injection and physiologicalsalt solution. Non-aqueous solutions or suspensions include propyleneglycol, polyethylene glycol, plant oil such as olive oil, alcohol suchas ethanol, POLYSORBATE80 (registered trade mark) etc.

[0149] Such compositions may comprise additional diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent, assisting agents such as assisting agents fordissolving (for example, glutamic acid, asparaginic acid). They may besterilized for example, by filtration through a bacteria-retainingfilter, by incorporation of sterilizing agents in the compositions or byirradiation. They may also be manufactured in the form of sterile solidcompositions which can be dissolved in sterile water or some othersterile diluent for injection immediately before use.

[0150] Other compositions for parenteral administration include liquidsfor external use, and endermic liniments, ointments, suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by known methods.

BEST MODE TO CARRY OUT THE INVENTION

[0151] The following Reference Examples and Examples are intended toillustrate, but not limit, the present invention.

[0152] The solvents in parentheses in chromatographic separations andTLC show the developing or eluting solvents and the ratios of thesolvents used are by volume.

[0153] The solvents in parentheses in NMR show ones used formeasurement.

REFERENCE EXAMPLE 1

[0154] (9 α, 15 α, 13E)-1-t-butyldimethylsilyloxy-9-hydroxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en

[0155] (9 α, 11 α, 15 α,13E)-6-Acetylthio-9-trimethylsilyloxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-1,2,3,4,5,17,18,19,20-nonanorprost-13-en(280 mg; prepared by the same procedure described in Reference Example27 in the specification of WO00/03980) and1-t-butyldimethylsilyloxy-4-iodobutane (345 mg) were dissolved intomethanol. Thereto, potassium carbonate (152 mg) was added. The mixturewas stirred for 2 hours at room temperature. After termination ofreaction, ether was added to reaction solution. The mixture was washedby water and a saturated saline solution, dried over by anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified with silica gel chromatography (hexane:ethyl acetate=4:1)to obtain the title compound (139 mg) having the following physicaldata.

[0156] TLC: Rf 0.52 (hexane:ethyl acetate=2:1);

[0157] NMR(CDCl₃): δ7.3-7.1 (m, 4H), 5.55-5.2 (m, 2H), 4.75-4.45 (m,1H),4.42 (s, 2H), 4.3-4.2 (m, 2H), 3.62 (t, J=5 Hz, 2H), 3.38 (s, 3H),3.4-3.2 (m, 2H), 3.0-2.7 (m, 2H), 2.6-2.4 (m, 4H), 2.4-2.2 (m, 1H),2.05-1.85 (m, 2H), 1.85-1.3 (m, 15H), 0.89 (s, 9H), 0.05 (s, 6H).

REFERENCE EXAMPLE 2 (15 α,13E)-1-t-butyldimethylsilyloxy-9-oxo-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en

[0158]

[0159] To a solution of (9 α, 15 α,13E)-1-t-butyldimethylsilyloxy-9-hydroxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en(139 mg; prepared in Reference Example 1) in ethyl acetate (1.0 ml),isopropyldiethylamine (0.24 ml) was added. The mixture was cooled withice. A solution of sulfur trioxide-pyridine complex (110 mg) indimethylsulphoxide (DMSO; 1 ml) was added at a dropwise thereto for 1minute. After stirring the mixture for 20 minutes, water was addedthereto. The mixture was extracted with ethyl acetate. The organic layerwas washed by 1N hydrochloric acid, water, a saturated solution ofsodium hydrogen carbonate, a saturated saline solution, succeedingly,dried over by magnesium sulfate, and concentrated under reduced pressureto obtain the title compound having the following physical data. TLC: Rf0.63 (hexane:ethyl acetate=2:1).

EXAMPLE 1 (15 α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol

[0160]

[0161] To a mixture solvent of acetonitlile (2 ml) and methanol (1 ml),(15 α,13E)-1-t-butyldimethylsilyloxy-9-oxo-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en(prepared in Reference Example 2) was dissolved. Thereto, 0.1Nhydrochloric acid (1 ml) was added. The mixture was stirred for 2 hoursat 35 ° C. After termination of reaction, a saturated solution of sodiumhydrogen carbonate was added thereto. The mixture was extracted withethyl acetate two times, washed by a saturated saline solution, driedover by magnesium sulfate and concentrated under reduced pressure. Theresidue was purified with silica gel chromatography (hexane:ethylacetate=1:2 to 1:3) to obtain the title compound (72 mg) having thefollowing physical data.

[0162] TLC: Rf 0.25 (ethyl acetate:hexane=2:1);

[0163] NMR(CDCl₃): δ7.3-7.1 (m, 4H), 5.75-5.6 (m, 2H), 4.44 (s, 2H),4.4-4.3 (m, 1H), 3.65 (t, J=6 Hz, 2H), 3.41 (s, 3H), 2.9-2.7 (m, 2H),2.7-2.3 (m, 6H), 2.3-2.0 (m, 3H), 2.0-1.5 (m, 9H).

EXAMPLES 1(1)-1(4)

[0164] By the same procedure as described in Reference Examples 1 and 2and Example 1, the compounds having the following physical data wereobtained.

EXAMPLE 1(1)

[0165] (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol

[0166] TLC: Rf 0.18 (ethyl acetate);

[0167] NMR(CDCl₃): δ7.35-7.17 (m, 4H), 5.77 (dd, J=15.0, 6.0 Hz, 1H),5.54 (dd, J=15.0, 8.0 Hz, 1H), 4.48-4.38 (m, 3H), 4.00-3.90 (m, 1H),3.68-3.63 (m, 2H), 3.42 (s, 3H), 3.01-2.21 (m, 11H), 1.92-1.55 (m, 8H).

EXAMPLE 1(2) (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methyl-4-hydroxy-phenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol

[0168]

[0169] TLC: Rf 0.19 (ethyl acetate:methanol=50:1);

[0170] NMR(CDCl₃): δ7.0-6.7 (m, 3H), 5.68 and 5.53 (dd, J=15, 8 Hz, 1H),5.57 and 5.35 (dd, J=15, 9 Hz, 1H), 4.2-3.9 (m, 2H), 3.65-3.6 (br, 2H),2.8-2.0 (m, 16H), 2.0-1.5 (m, 6H), 1.32 and 1.20 (d, J=7 Hz, 3H).

EXAMPLE 1(3) (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol

[0171]

[0172] TLC: Rf 0.08 (ethyl acetate);

[0173] NMR(CDCl₃): δ7.36-7.10 (m, 4H), 5.71 (dd, J=15.3, 6.6 Hz, 0.5H),5.62 (dd, J=15.6, 5.7 Hz, 0.5H), 5.53 (dd, J=16.0, 8.1 Hz, 0.5H), 5.47(dd, J=15.3, 7.8 Hz, 0.5H), 4.49-4.38 (m, 2H), 4.25-4.15 (m, 1H),3.99-3.76 (m, 1H), 3.71-3.60 (m, 2H), 3.43 (s, 3H), 3.35-3.23 and3.10-2.41 (m, 8H), 2.36-2.14 (m, 4H), 2.00-1.60 (m, 6H), 1.36 and 1.28(d, J=7.0 Hz, 3H).

EXAMPLE 1(4) (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-2,3-propano-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol

[0174]

[0175] TLC: Rf 0.22 (ethyl acetate:methanol=20:1);

[0176] NMR(CDCl₃): δ7.38-7.10 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz, 1H),5.53 (dd, J=15.3, 8.0 Hz, 1H), 4.48-4.38 (m, 3H), 4.00-3.89 (m, 1H),3.63-3.53 (m, 1H), 3.46-3.17 (m, 5H), 2.95-2.14 (m, 11H), 1.99-1.62 (m,3H),1.06-0.84 (m, 2H), 0.58-0.44 (m, 2H).

FORMULATION EXAMPLE 1

[0177] The following compounds were admixed in conventional method andpunched out to obtain 100 tablets each containing 0.5 mg of activeingredient. (11α,15α,13E)-9-oxo-11,15- 250 mg (active ingredient 50 mg)dihydroxy-16-(3-methoxy- methylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol · α- cyclodextrin Carboxymethylcellulosecalcium 200 mg Magnesium stearate 100 mg Micro crystalline cellulose 9.2 g

FORMULATION EXAMPLE 2

[0178] The following components were admixed in a conventional method,and the solution was sterilized in a conventional method, placed 1 mlportions into ampoules and freeze-dried in a conventional method toobtain 100 ampoules each containing 0.2 mg of active ingredient.(11α,15α,13E)-9-oxo-11,15- 100 mg (active ingredient 20 mg)dihydroxy-16-(3-methoxy- methylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-alcohol · α- cyclodextrin Mannit  5 g Distlled water100 ml

1. A 5-thia-ω-substituted phenyl-prostaglandin E alcohol of the formula(I)

(wherein, --A-- is absent or --A-- is methylene or ethylene, R¹ ishydrogen, C1-6 alkyl, phyenyl-C1-6 alkyl, C2-6 alkanoyl, or phyenyl-C2-6alkanoyl, R² is oxo or halogen, R³ is hydrogen or hydroxy, R^(4a) andR^(4b) are, independently, hydrogen or C1-4 alkyl, R⁵ is phenylsubstituted with the following group: i) 1-3 of group selected from thegroup consisting of C1-4 alkyloxy-C1-4 alkyl, C2-4 alkenyloxy-C1-4alkyl, C2-4 alkynyloxy-C1-4 alkyl, C3-7 cycloalkyloxy-C1-4 alkyl, C3-7cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl, phenyloxy-C1-4 alkyl, phyenyl-C1-4alkyloxy-C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl, C2-4 alkenylthio-C1-4alkyl, C2-4 alkynylthio-C1-4 alkyl, C3-7 cycloalkylthio-C1-4 alkyl, C3-7cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl, phenylthio-C1-4 alkyl, andphyenyl-C1-4 alkylthio-C1-4 alkyl, ii) C1-4 alkyloxy-C1-4 alkyl and C1-4alkyl, C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy, C1-4 alkyloxy-C1-4alkyl and hydroxy, C1-4 alkyloxy-C1-4 alkyl and halogen, C1-4alkylthio-C1-4 alkyl and C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl and C1-4alkyloxy, C1-4 alkylthio-C1-4 alkyl and hydroxy, or C1-4 alkylthio-C1-4alkyl and halogen, iii) haloalkyl or hydroxy-C1-4 alkyl, or iv) C1-4alkyl and hydroxy;

is a single bond or a double bond) or cyclodextrin clathrate thereof. 2.The compound according to claim 1, wherein R² is oxo.
 3. The compoundaccording to claim 1, wherein R² is halogen.
 4. The compound accordingto claim 1, wherein R³ is hydrogen.
 5. The compound according to claim1, wherein R³ is hydroxy.
 6. The compound according to claim 1, whereinR⁵ is phenyl substituted with i) 1-3 of substituent(s) selected fromC1-4 alkyloxy-C1-4 alkyl, C2-4 alkenyloxy-C1-4 alkyl, C2-4alkynyloxy-C1-4 alkyl, C3-7 cycloalkyloxy-C1-4 alkyl, C3-7cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl, phenyloxy-C1-4 alkyl, phyenyl-C1-4alkyloxy-C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl, C2-4 alkenylthio-C1-4alkyl, C2-4 alkynylthio-C1-4 alkyl, C3-7 cycloalkylthio-C1-4 alkyl, C3-7cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl, phenylthio-C1-4 alkyl, orphyenyl-C1-4 alkylthio-C1-4 alkyl.
 7. The compound according to claim 1,wherein R⁵ is phenyl substituted with ii) C1-4 alkyloxy-C1-4 alkyl andC1-4 alkyl, C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy, C1-4alkyloxy-C1-4 alkyl and hydroxy, C1-4 alkyloxy-C1-4 alkyl and halogen,C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl andC1-4 alkyloxy, C1-4 alkylthio-C1-4 alkyl and hydroxy, or C1-4alkylthio-C1-4 alkyl and halogen
 8. The compound according to claim 1,wherein R⁵ is phenyl substituted with iii) haloalkyl, or hydroxy-C1-4alkyl.
 9. The compound according to claim 1, wherein R⁵ is phenylsubstituted with iv) C1-4 alkyl and hydroxy.
 10. The compound accordingto claim 1, which is (15 α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,(11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,(11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methyl-4-hydroxyphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,(11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,or (11 α, 15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-2,3-propano-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol.11. A process which comprises reacting a compound of the formula (II)

(wherein, R¹⁻¹ is C1-6 alkyl, phenyl-C1-6 alkyl, C2-6 alkanoyl,phenyl-C2-6 alkanoyl, or a protecting group of hydroxy which is removedunder an acidic condition, R³⁻¹ is hydrogen, or hydroxy protected by aprotecting group of hydroxy which is removed under an acidic condition,R¹⁰ is a protecting group of hydroxy which is removed under an acidiccondition, R⁵⁻¹ is the same meaning of R⁵ in claim 1 provided that ahydroxy in the group represented by R5-1 is protected by a protectinggroup of hydroxy which is removed under an acidic condition, and theother symbols are the same meaning as defined hereinbefore) for removalof a protecting group under an acidic condition to obtain a compound ofthe formula (I)

(wherein, all the symbols are the same meaning as defined in claim 1).12. A pharmaceutical composition comprising a 5-thia-ω-substitutedphenyl-prostaglandin E alcohol of the formula (I), or cyclodextrinclathrate thereof as an active ingredient.